Anemias in the elderly are an important clinical problem affecting around 3 million patients in the US. About 25% of these have biochemical markers of anemia of inflammation: the combination of decreased serum iron with normal or elevated ferritin. In many elderly the anemia appears to be caused by an age-related increase in inflammation not related to clinically-evident inflammatory diseases but characterized by increased concentrations of IL-6. We designate this disorder as anemia of unexplained inflammation (ADI) to differentiate it from unexplained anemia (UA) in which iron parameters are normal and there is no evidence of inflammation. We propose that ADI is a state of relative resistance to erythropoietin (EPO) due to inflammation-induced restriction of iron supply to the bone marrow. Suppression of EPO production may further exacerbate AUI. Clinical experience suggests that the iron block in moderate inflammation can be overcome by pharmacologic doses of EPO but it is not known by what mechanism EPO counteracts the IL- 6/hepcidin axis to release iron for erythropoiesis. The goal of this proposal is to elucidate the pathogenesis of AUI and the mechanisms of its response to EPO, and to identify the mechanisms of crossregulation between EPO and the IL-6/ hepcidin axis. We propose a series of experiments in human subjects and animal models: Specific Aim 1: Analyze the interaction of inflammation and EPO in the pathogenesis and treatment of anemia in the elderly Specific Aim 2: In mice with anemia of inflammation, analyze the interactions of hepcidin and EPO Specific Aim 3: In mice with anemia of inflammation, analyze the interactions of IL-6 and EPO Specific Aim 4: In transgenic mice, characterize the effect of inducible chronic IL-6 excess on iron metabolism and resistance to EPO Anemia in the elderly is a common condition that impairs their health, independence and quality of life. This study is designed to find how inflammation causes anemia in the elderly and how the disease processes are changed by available treatments.